Multi-Part Lyophilization Container And Method Of Use

ABSTRACT

Provided is a multi-part lyophilization container for lyophilizing a fluid, storing the lyophilizate, reconstituting the lyophilizate, and infusing the reconstituted lyophilizate into a patient, including a method of using same. The container includes a front surface, a back surface, a non-breathable section including a port region, a breathable section including a breathable membrane, and a peelable region including a peelable seal encompassing a boundary between the non-breathable section and the breathable section. The method includes inputting a fluid into a non-breathable section of the container, freezing the fluid, applying, in a lyophilization chamber, vacuum pressure, opening the peelable seal using a pressure differential, applying heat energy, sublimating the fluid and creating a temporary occlusion in a peelable region of the container.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/818,214, entitled “Multi-part Lyophilization Container and Methodof Use,” filed in the U.S. Patent and Trademark Office on Mar. 14, 2019,U.S. Provisional Patent Application No. 62/952,752, entitled“Lyophilization Loading Tray Assembly and System,” filed in the U.S.Patent and Trademark Office on Dec. 23, 2019 and Provisional PatentApplication No. 62/971,072, entitled “Lyophilization Container FillFixture, System and Method of Use,” filed in the U.S. Patent andTrademark Office on Feb. 6, 2020, each of which is incorporated byreference herein in its entirety.

The invention was made with government support under contract numberH92222-16-C-0081 awarded by the United States Department of Defense. Thegovernment has certain rights in the invention.

BACKGROUND

The present application describes a device and related system and methodfor lyophilizing and storing a fluid. The device is a continuallyevolving, multi-section lyophilization container including a peelableseal. The container evolves throughout the stages of filling,lyophilization, storage, reconstitution and infusion. The methoddescribes the manipulation of the container throughout thelyophilization process.

Any suitable fluid may be lyophilized and stored using the devices andtechniques described in this disclosure, including human and animalblood and related blood products, such as blood plasma.

Many lyophilization containers and associated techniques are known inthe art. Many of these containers and techniques include a breathablemembrane and are resultantly vulnerable to a reduction in containerperformance if the breathable membrane becomes compromised. Whenlyophilizing human or animal blood, or a component thereof, membranefouling and an associated diminution in container performance can occurif there is direct contact between the blood and breathable membranematerial. Accordingly, various lyophilization techniques and deviceshave been devised which maintain a separation between the breathablemembrane material and blood plasma. For example, one approach utilizes aflexible lyophilization container incorporating a semi-rigid columnarmember within the container cavity. When the container is horizontallydisposed on a lyophilizer shelf, the columnar member extends upwardcreating a support which maintains a framed piece of breathable membraneabove the liquid plasma. Another approach utilizes a rigidlyophilization tray including a breathable roof. The rigidity ofcontainer components causes the roof to be maintained above the plasmathroughout lyophilization.

Notably, these techniques are vulnerable to operator error. That is, aninadvertent tilting of the container during pre-load or while intransport may result in membrane fouling. Moreover, these techniquesrequire relatively expensive disposable equipment. Accordingly, thereexists a need for an improvement in lyophilization container design.

Although specific embodiments of the present application are provided inview of these and other considerations, the specific problems discussedherein should not be interpreted as limiting the applicability of theembodiments of this disclosure in any way.

SUMMARY

The lyophilization container of the present application describesimprovements upon previous container configurations by using a peelableseal in a peelable container region to create an initial occlusion inthe container resulting in the isolation of a subject liquid (e.g.,blood plasma) in only a non-breathable container section prior tofreezing.

This summary is provided to introduce aspects of some embodiments of thepresent application in a simplified form and is not intended to comprisean exhaustive list of all critical or essential elements of the claimedinvention, nor is it intended to limit the scope of the claims.

Embodiments provide for a multi-part lyophilization container. Thecontainer includes a front surface, a back surface, a non-breathablesection including a port region, a breathable section including abreathable membrane, and a peelable region including a peelable sealencompassing a boundary bridging the non-breathable section and thebreathable section. The non-breathable section is configured toaccommodate any of a liquid, a solid and a gas, whereas the breathablesection is configured to accommodate only a gas.

In another aspect, provided is a method of lyophilizing a fluid in amulti-part container. The method includes inputting a fluid into anon-breathable section of the container, freezing the fluid, applying,in a lyophilization chamber, vacuum pressure, opening the peelable sealusing a pressure differential, applying heat energy, sublimating thefluid and creating a temporary occlusion in a peelable region of thecontainer.

In yet another aspect, provided is a method of manufacturing a peelableseal in a multipart lyophilization container. The method includesapplying heating elements of a heat-sealing machine to opposingmaterials of the container at a continuous temperature of approximately64° C. for approximately 40 seconds.

Further embodiments of the present application include additionaldevices, methods and systems for lyophilizing fluids. The fluid may beany suitable liquid, including human or animal plasma.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting and non-exhaustive embodiments are described with referenceto the following figures.

FIG. 1 is a plan view of a lyophilization container according to anembodiment of the present application;

FIG. 2 is a perspective view of the lyophilization container of FIG. 1 ;

FIG. 3A is a plan view of a non-breathable section of a lyophilizationcontainer according to an embodiment of the present application;

FIG. 3B is an expanded view of the port region of the non-breathablesection of the lyophilization container of FIG. 3A;

FIG. 4 is a plan view of a breathable section of a lyophilizationcontainer according to an embodiment of the present application;

FIG. 5 is a section view of the Hold Open Device (HOD) of the embodimentshown in FIG. 4 ;

FIG. 6 is a side section view of an alternative configuration of apeelable region according to an embodiment of the present application;

FIG. 7 is an illustration of a system for lyophilizing a fluid accordingto an embodiment of the present application;

FIG. 8 is a workflow schematic illustrating a lyophilization processaccording to an embodiment of the present application; and

FIG. 9 is workflow schematic illustrating a lyophilization processaccording to another embodiment of the present application.

DETAILED DESCRIPTION

The principles described in the present application may be furtherunderstood by reference to the following detailed description and theembodiments depicted in the accompanying drawings. Although specificfeatures are shown and described below with respect to particularembodiments, the present application is not limited to the specificfeatures or embodiments provided. Moreover, embodiments below may bedescribed in connection with the lyophilization and storage of human oranimal blood or a component thereof; however, such descriptions aremerely illustrative. For example, embodiments may be utilized inconnection with blood plasma, a fluid including cryoprecipitate, a fluidincluding lysed platelets or a cell suspension, but are not limitedthereto. Those of skill in the art will appreciate that embodiments ofthis disclosure may be used in connection with the lyophilization of anysuitable fluid or liquid or component thereof.

Embodiments of the present application refer to a closed, sterilecontainer, including sterile fluid pathways, for lyophilizing andstoring a fluid. Embodiments described in this application may beimplemented in conjunction with many conventional, commerciallyavailable lyophilizers, including a Magnum® lyophilizer by MillrockTechnology, Inc. Further advantages of the various enumeratedembodiments are noted throughout this disclosure.

The terms “multi-part container,” “container,” “lyophilizationcontainer,” “multi-part lyophilization container,” and the like, areused interchangeably throughout this disclosure. Similarly, the term“breathable,” with respect to materials and membranes, may be usedinterchangeably with the term “semi-permeable,” whereas the term“non-breathable” may be used interchangeably with the term“non-permeable.” The term “peelable seal” may be used interchangeablywith the term “peel seal.”

FIG. 1 is plan view of a lyophilization container according to anembodiment of the present application.

Referring to FIG. 1 , the lyophilization container 100 includes anon-breathable section 102, including a port region 104; a breathablesection 106, including a Hold Open Device (HOD) 108, HOD capture zones110, a breathable membrane 112, an inner membrane weld 114 and handlerecesses 116; an outer perimeter weld 118; a peelable region 120 and atear-away tail 122.

As shown in FIG. 1 , the lyophilization container 100 is comprised oftwo principal sections: non-breathable section 102 and breathablesection 106, joined at peelable region 120. In a native or initialstate, the internal cavities of non-breathable section 102 andbreathable section 106 are isolated from one another by a temporarypeelable seal in peelable region 120. In a non-native or open state, thetemporary peelable seal of peelable region 120 has been removed and theinternal cavities of non-breathable section 102 and breathable section106 are in fluid communication with one another. Port region 104 definesan area within non-breathable section 102 that is configured toincorporate one or more fluidic ports. HOD 108 is a semi-rigid fixturewhich facilitates vapor flow in the container, and which is held inplace by HOD capture zones 110. Tear away tail 122 is a container regionconfigured to be torn away from breathable section 106 and whichincludes a hanger hole for hanging. Handle recesses 116 are configuredto cooperate with optional system components such as a fill fixture (asshown in FIG. 7 ). Breathable membrane 112 is incorporated intobreathable section 106 by inner membrane weld 114, which is a hermeticseal. Outer perimeter weld 118 is also a hermetic seal and defines theouter perimeter of the non-breathable section 102 and the breathablesection 106, including the port region 104.

The overall length of the lyophilization container 100, denoted as “L”is approximately 50 cm. In embodiments, overall length may be anydimension suitable for placement of the container in a shelf lyophilizeror other lyophilizer, any dimension suitable for increasing ordecreasing vapor flow resistance, or any dimension suitable forincreasing or decreasing the thickness of the frozen liquid, such asbetween 30 cm and 70 cm, or more preferably between 40 cm and 60 cm.

In the example shown, the length of non-breathable section 102, measuredfrom the midpoint of the peelable region, is approximately 28 cm. Inembodiments, the length of non-breathable section 102 may be anysuitable dimension, such as between 20 cm and 40 cm, or more preferably,between 24 cm and 32 cm. The length of breathable section 106, measuredfrom the midpoint of the peelable region and including tear away tail122, is approximately 22 cm. In embodiments, the length of breathablesection 106 may be any suitable dimension, such as between 10 cm and 30cm, or more preferably, between 18 cm and 26 cm.

In the embodiment shown, the widest portion of the container, denoted as“W_(MAX),” is approximately 14 cm and exists in the non-breathablesection 102. In embodiments, W_(MAX) may be any suitable dimension, suchas between 10 cm and 20 cm, or more preferably, between 13 cm and 17 cm.In the embodiment shown, the narrowest portion of the container, denotedas “W_(MIN),” is approximately 7 cm and exists in handle recesses 116.In embodiments, W_(MIN) may be any suitable dimension, such as between 5cm and 12 cm, or more preferably, between 6 cm and 10 cm. The exemplarycontainer dimensions of 14 cm by 50 cm described above are suited tolyophilize approximately 200 ml-300 ml of liquid plasma. Thelyophilization of larger or smaller volumes would suggest differentpreferred dimensions.

The “top” or “front” of the lyophilization container 100 shown isessentially identical to the “bottom” or “back” of the container 100.That is, each of the top and the bottom of the container includesnon-breathable material of the non-breathable section and breathablemembrane of the breathable section. In alternative embodiments, thebreathable membrane comprises a continuous sheet including an isoclinal(i.e., hairpin) fold causing the breathable membrane to bridge a portionof the top or front surface and a portion of the bottom or back surface.In yet another alternative embodiment, the breathable section mightcomprise breathable membrane only on the top of the container or only onthe bottom of the container. In operation, the lyophilization container100 is typically placed on a lyophilizer shelf such that the bottom orback of the container faces the lyophilizer shelf That is, duringlyophilization, a portion of each of the non-breathable section 102 andthe breathable section 106, including breathable membrane, face thelyophilizer shelf. Non-breathable section 102 should be in sufficientdirect or indirect thermal communication with the lyophilizer shelf tofacilitate conductive and/or radiative heat transfer. In yet furtherembodiments, only the non-breathable section might be in contact withthe shelf and the breathable section might reside off the shelf. Incertain other embodiments, the lyophilization container may be disposedvertically within a lyophilization chamber.

In operation, lyophilization container 100 exchanges fluids via portspositioned in the port region 104 of non-breathable section 102. Fluidexchanges occur only during initial filling of the container with liquidplasma and during the post-lyophilization filling of the container withsterile water for reconstitution and transfusion into a patient. Bothprior to, and after, the sublimation of the frozen fluid and removal ofvapor during lyophilization, non-breathable section 102 and breathablesection 106 are isolated from one another. Prior to sublimation,non-breathable section 102 and breathable section 106 are isolated fromone another by the temporary occlusion formed by a peelable seal inpeelable region 120. After sublimation, a clamp is used to create theocclusion of the container in the peelable region 120 encompassing thetransition between the non-breathable section 102 and breathable section106. In this respect, the position of the occlusion in the peelableregion 120 defines the boundary between non-breathable section 102 andbreathable section 106.

Outer perimeter weld 118 defines the outer perimeter of the container,except tear away tail 122 in certain embodiments, and includes portregion 104 of the non-breathable section 102. Outer pperimeter weld 118has an average width of approximately 7 mm. In embodiments; however,outer perimeter weld 118 may be any suitable width, such as between 2 mmand 12 mm, and may further be variable by up 3 mm along its length.

Inner membrane weld 114 surrounds the breathable membrane 112 withinbreathable section 106. Inner membrane weld 114 also has average widthof approximately 7 mm; however, in embodiments, inner membrane weld 114may be any suitable width, such as between 2 mm and 12 mm, variable byup 3 mm along its length.

Port region 104 is the portion of the outer perimeter weld 118 ofnon-breathable section 102 configured to incorporate one or more fluidicports capable of forming a sterile fluid pathway between thelyophilization container and any of several other fluid containers. Portregion 104 is also configured to facilitate transfusion to a patient.

In addition to encompassing the boundary between non-breathable section102 and breathable section 106, peelable region 120 is adapted tofacilitate the evolution of the container throughout its life cycle.Occlusion of the container 100 in the peelable region 120, eitherinitially by the intact peelable seal, or by subsequent occlusion (e.g.,clamping), creates a temporary impermeable or substantially impermeableseal, eliminating fluid communication between the non-breathable section102 and breathable section 106. That is, in operation, an initialocclusion created by an intact peelable seal isolates non-breathablesection 102 from the breathable section 106 prior to the introduction offluid via ports in port region 104. Upon formation of a frozen icestructure (i.e., a frozen fluid structure to be lyophilized) a pressuredifferential is generated by the application of vacuum in thelyophilization chamber resulting in an opening of the temporary peelableseal. In this unoccluded state, the container includes a generous, openpathway for vapor flow between the non-breathable section 102 andbreathable section 106. Prior to opening the lyophilization chamber, thecontainer is again occluded (e.g., by a clamp) in the peelable region120. The ability of the container to continually evolve in form andfunction ensures that no contact occurs between the subject fluid andthe breathable section 106 by causing the subject liquid to be isolatedand frozen in only the non-breathable section 102 and allowing only thevapor flow from sublimation and desorption to contact the breathablesection 106. That is, embodiments of the present application areconfigured to create a continuous physical separation between thesubject fluid and the breathable section 106. Accordingly, thenon-breathable section 102 is adapted to accommodate any of a solid, aliquid or a gas, whereas the breathable section 106 is adapted toaccommodate only a gas (i.e., a gas only section).

Peelable region 120 is approximately 1 cm in width; however, inembodiments, the peelable region 120 may be between 0.5 cm and 3.0 cmwide, such as between 0.8 cm and 1.5 cm wide. The nearest edge of thepeelable region 120 is preferably positioned within 5 cm of thebreathable membrane 112 of the breathable section 106 but may bepositioned between 0.2 cm and 10 cm, such as between 3 cm and 7 cm, fromthe breathable membrane 112. The peelable region 120 should besufficiently proximate to the breathable membrane 112 to ensure theefficient use of container materials and to minimize the distance thatvapor must flow to exit the container, yet sufficiently distant from thebreathable membrane 112 to allow for the creation of a permanent seam innon-breathable material between the occlusion and the breathablemembrane post lyophilization. The creation of a permanent seam innon-breathable material between the occlusion and the breathablemembrane material post-lyophilization creates a permanent seal, allowingfor a permanent separation of container sections and the removal anddisposal of the breathable section 106. Removal of the breathablesection 106 is a further step in the evolution of the container. Removalof the breathable section 106 minimizes the volume and the mass of thefinal product, which is desirable for both transportation and storage.Additionally, removal of breathable section 106 transformsnon-breathable section 102 into a more traditional container suitablefor fluid transfusion into a patient. In embodiments, tear away tail 122may optionally be removed from breathable section 106 and may furtheroptionally be attached to non-breathable section 102 in order to createa means by which the final container can be hung by an operator. Thesubsequent attachment of the tear away tail 122 to the breathablesection 102 may be performed using any suitable equipment, including theheat-sealing equipment used to create the permanent seam created tocontain the final product in the non-breathable section 102.

In embodiments, the initial presence of an intact peelable seal in thepeelable region 120 may provide a visual indicator demarcating theposition of the peelable region 120. However, embodiments may includeone or more additional position indicators. For example, the peelableregion 120 may further be indicated by lines, by a color scheme, or byany other conventional means of visual indication. In embodiments, achoice of material or texture may further indicate the position of thepeelable region 120. For example, a bumped, an etched, or any other typeof surface texture or treatment may provide an indication of theposition and boundaries of the peelable region 120. In embodiments, anyof such position indicators, materials, textures or the like may also bechosen for one, or both, of the inner or outer surfaces of containermaterial in the peelable region 120 to impart improved sealingcharacteristics (e.g., smooth materials), to impart an improved abilityof the materials to pull apart from one another, or to pull apart fromice formed during freezing of the subject fluid (e.g., texturedmaterials). In embodiments, an opened peel seal may expose or result insmooth surfaces in a peelable region which may be a favorable conditionfor a subsequent occlusion by a clamp. Material and design choices forthe peelable region 120 should consider that the initial intact peelableseal and the subsequent occlusion created in the peelable region 120must reliably form a temporary impermeable seal. However, it should benoted that in some circumstances, an occlusion may not be a perfectlyimpervious or hermetic barrier or seal. That is, in certain situations,minor or insubstantial leakage across an occlusion may be acceptable.

As noted, the initial occlusion of the container in the peelable region120 is provided by an intact peelable seal. Subsequent occlusion in thepeelable region 120 occurs by other means, such as by manual clamping orby various automated or semi-automated means. Exemplary manual clampsmay include, but are not limited to, screw clamps or bag clips that arein common usage. Further exemplary clamps may include specializedclamps, such as a two-piece guillotine clamp. Various automated orsemi-automated occlusion means may, for example, include mechanicalcompression means incorporated into or actuated by the shelves of, orthe shelf system of, a lyophilizer. Such means of occlusion may operatein conjunction with a lyophilization loading tray or tray assembly, suchas that shown in FIG. 7 .

In the embodiment shown in FIG. 1 , the non-breathable material isethylene-vinyl acetate (EVA). EVA exhibits several advantageousproperties including its relative strength, its relative elasticity andresilience at low temperatures, its relative crack resistance and theease with which it may be manufactured. EVA also exhibits comparativelyfavorable thermal transfer properties. Nonetheless, in embodiments,material choices for non-breathable material are not limited, and mayinclude a variety of non-breathable materials that exhibit preferablecharacteristics, such as thermoplastic elastomers (TPEs). TPEs arerelatively soft and flexible, and exhibit advantages for severalhealthcare applications. For instance, TPEs can be sterilized usingautoclaves, gamma irradiation, or ethylene oxide. Further, TPEs can bedesigned to be biocompatible, to have high purity, and to have lowlevels of extractable and leachable substances. TPEs are also recyclableand are a comparatively favorable material for cryogenic storage.

Linear, low density polyethylene (LLDPE) may also be desirable for useas non-breathable material. LLDPE is preferable to certain othermaterials due to its favorable puncture and impact resistance and to itshigh tensile strength. For instance, as compared to LDPE, LLDPE exhibitssuperior flexibility and resistance to cracking, thus making it moresuitable for certain thin film applications.

Materials selected for non-breathable material must maintain strength atlow temperatures (e.g., −30° C. to −60° C.) as is required forlyophilization. Certain materials exhibiting a low surface energy andsuper-hydrophobicity may further be incorporated into the interiorsurface of the non-breathable section to facilitate an improved releaseof the ice structure from the inner surfaces of the container afterfreezing and before drying.

In embodiments, various additional or alternative plastic films may beincorporated into non-breathable section 102, or to all areas of thecontainer with non-breathable material for a particular purpose orapplication. For example, materials may be implemented for any ofimproved impermeability, improved heat-sealing characteristics orimproved mechanical strength. In yet further embodiments, variousadditional features may also be included in non-breathable section 102.For instance, a section of relatively clear container material may beincorporated into non-breathable section 102 to allow visual inspectionof the subject fluid before, during or after lyophilization.

Notably, an initial intact peelable seal may require specific materialand design choices to function optimally under lyophilizationconditions. In a preferred embodiment, the peel seal is constructedusing dissimilar top and bottom materials. Dissimilar top and bottommaterials may more easily and reliably peel away from one another undervacuum. In embodiments using the same or similar top and bottommaterials, an additive (e.g., a slip agent) may be applied to one of thematerials in order to achieve improved peeling characteristics undervacuum. In another preferred embodiment, the seal may further includematerials having dissimilar textures. For instance, the top material ofa peelable seal may comprise a bumped or etched texture, and the bottommaterial may comprise a smooth texture, or vice versa. In embodiments,dissimilar materials and dissimilar textures may be implementedsimultaneously.

In embodiments, specific manufacturing parameters may further berequired to generate a desirable peelable seal. Preferably, a peelableseal is 0.95 cm in width (+/−0.076 cm); however, the width of thepeelable seal may vary depending upon various factors, such as the typeof fluid to be lyophilized, choice of container materials, etc. Inembodiments, the manufacture of a peel seal using a heat seal machinemay require the heating elements (i.e., heat bars) of the heat sealer tobe applied to the container materials within a particular range oftemperature, pressure and duration. In a preferred embodiment, heatingelements are maintained at a temperature of approximately 64° C.(+/−0.25° C.) and applied to container materials at a pressure ofapproximately 50 psi for 40 seconds. In further embodiments, however,these parameters are not limited and may vary according to a particularapplication. For instance, heating element temperature may be between60° C. and 70° C., such as between 63° C. and 67° C. Likewise, clampingpressure may be between 30 psi and 80 psi, such as between 40 psi and 70psi. Similarly, clamping duration may occur over a time range of between10 seconds and 90 seconds, such as between 40 seconds and 70 seconds.

Because impulse or discontinuous heat may result in cross linking of thematerial and a resultant malfunction, the temperature of the heatingelements is preferably maintained continuously within a narrow range. Toachieve a continuous heat source, embodiments of the heat seal machinemay be specialized to include a relatively large amount of materialcapable of storing sufficient heat energy to recover quickly from theinitial temperature drop caused by initial contact with the relativelycool container material, yet which does not overcompensate with asubsequent addition of excess heat. For example, a customized orspecialized heat seal machine may be required, and which comprises oneor more large metal components as part of its clamping or sealingmechanism. In embodiments, the metal component(s) may be heated usingvarious conventional means such as an electrical strip or a liquidsource such as water, glycol, or other substance capable of storingsufficient energy. In further embodiments, indirect means such asinfrared or RF may be applied to heat the metal component(s).Alternative indirect means for creating the peelable seal in the absenceof the metal component(s) may include ultrasonic welding and laserapplications.

In embodiments, the above-described combination of material choices andmanufacturing parameters are preferred for a seal measuring 0.95 cm inwidth (+/−0.076 cm) and may result in a peelable seal which opensreliably and evenly across its length under lyophilization conditions(e.g., at lyophilization chamber pressures of between 400 Torr and 100Torr and lyophilization chamber temperatures of between −30° C. and −60°C.).

FIG. 2 is a perspective view of the lyophilization container of FIG. 1 .

Referring to FIG. 2 , the lyophilization container 200 includes anon-breathable section 202, including a port region 204; a breathablesection 206, including a Hold Open Device (HOD) 208, HOD capture zones210, a breathable membrane 212, an inner membrane weld 214 and handlerecesses 216; an outer perimeter weld 218; a peelable region 220 and atear-away tail 222.

Although FIG. 1 and FIG. 2 depict an irregularly shaped container,further embodiments may comprise a more regular geometry, such as anessentially rectangular shape. Additional container configurations mayalso include alternative irregularities, e.g., the dimensions orgeometry of a particular region or feature may be altered to achievedesign or performance objectives. A variety of container modificationsmay be understood by one of skill in the art to be within the scope andspirit of this application.

FIG. 3A is a plan view of a non-breathable section of a lyophilizationcontainer according to an embodiment of the present application.

Referring to FIG. 3A, non-breathable section 300 comprises anon-breathable material 302; and an outer perimeter weld 304, includinga port region 306 incorporating fluidic ports 308; and a portion of apeelable region 310.

Non-breathable section 300 is comprised of the non-breathable materialdescribed above. The boundaries of non-breathable section 300 includeouter perimeter weld 304, including port region 306, and the midpoint(i.e., the estimated position of an occlusion) of the peelable region310. That is, when the container is occluded in the peelable region 310,non-breathable section 300 may be defined as the section of thecontainer on the side of the occlusion that is non-breathable. When anocclusion is not present in the peelable region 310, the boundary of thenon-breathable section may be approximated as the midpoint of thepeelable region 310, as shown in FIG. 3A.

FIG. 3B is an expanded view of the port region of the non-breathablesection of the lyophilization container of FIG. 3A.

Referring to FIG. 3B, port region 306 includes three ports 308. Theports 308 define the manner in which the lyophilization containerexchanges fluids with other vessels and containers. The ports 308 mustaccordingly provide secure, sterile connections which eliminate thepotential for breakage, contamination or misconnection, and mustfunction across every phase of use including filling, lyophilization,storage, reconstitution and, in the case of lyophilized plasma,infusion. In embodiments, the configuration and number of ports 308 mayvary depending on a particular application. For instance, embodimentsmay include between 1-5 ports, such as 3 ports. Ports 308 may furtherinclude connections which are either resealable or non-resealable.

Ports 308 shown in FIG. 3B may be adapted to include a variety of ports.For example, ports 308 may include any of a spike port, a docking portand a reconstitution port. A spike port may be included to facilitatereinfusion of a reconstituted blood product into a patient. An exemplaryspike port may be any weldable spike port known in the art which iscompatible for use in lyophilization containers. Examples of suitablematerials for use in spike port include polyvinyl chloride (PVC) andethylene-vinyl acetate (EVA) (e.g., such as is manufactured by Carmo ofDenmark). In other embodiments, a polypropylene (PP) spike port may bedesirable.

A docking port may be included to connect the lyophilization containerwith another fluid container, such as a blood pooling container orpooling container set. A docking port may further be used to introduceair o+r other gas into the lyophilization container. Air or other gasmay, for example, be introduced to create a vapor space above thesubject liquid or to regulate pH. An exemplary docking port comprisesPVC tubing. In embodiments, however, dock port may include any suitabledocking fixtures or tubing which are known in the art.

A reconstitution port may be included to accept an inflow ofreconstitution fluid into the lyophilization container. An exemplaryreconstitution port 308 may include a male or a female Luer-Lock typeconnection in order to prevent accidental misconnection. One example ofsuch a connection is the Correct Connect® system that is a standardizedconnection system used in apheresis applications. In embodiments,various one-way valves and other means for providing an error proofconnection may also be adapted for use with the reconstitution port 308.Notably, the type of connection used for reconstitution is particularlyimportant. That is, the handling of reconstitution fluids entails thepotential risk of a direct transfusion of the reconstitution fluid intothe patient. Such an event constitutes a serious and immediate healthhazard. For this reason, it is important that the reconstitution portand related connections be highly conspicuous and be incompatible withthe other ports in order to avoid an occurrence of accidentalmisconnection.

FIG. 4 is a plan view of a breathable section of a lyophilizationcontainer according to an embodiment of the present application.

Referring to FIG. 4 , breathable section 400 comprises an outerperimeter weld 402; a Hold Open Device (HOD) 404; HOD capture zones 406;a breathable membrane 408; an inner membrane weld 410; a tear away tail412; handle recesses 414; a hanger hole 416; a tear seam 418; and aportion of a peelable region 420.

The midpoint (i.e., estimated position of occlusion) of the peelableregion 420 constitutes a boundary of breathable section 400. That is,when the container is partitioned in the peelable region 420 by eitheran intact peelable seal or by a subsequent occlusion, breathable section400 may be defined as the section of the container on the side of theocclusion that is breathable. When an occlusion is not present in thepeelable region 420, the boundary of the breathable section 400 may beapproximated as the midpoint of the peelable region, as shown in FIG. 4. Notably, although tear away tail 412 is not itself breathable, it maybe considered part of breathable section 400 for convenience and for itsattachment thereto.

Breathable section 400 comprises breathable membrane 408 embedded withinnon-breathable material. Inner membrane weld 410 is a sterile sealdefining the boundary between the breathable membrane and non-breathablematerial. Outer perimeter weld 402 is a sterile seal defining the outerperimeter of breathable section 400.

In certain embodiments, breathable membrane 408 may comprise only onematerial. In other embodiments, breathable membrane 408 may comprise twoor more materials, for example, breathable membrane may comprise amembrane laminate consisting of a breathable membrane and a backingmaterial. In embodiments comprising a laminate, membrane material mayinclude p (PTFE) or expanded p (ePTFE). ePTFE membranes are preferableto other membranes for several reasons. For instance, ePTFE provides amicrostructure that may be precisely controlled, which results in theability to obtain a desired a pore size distribution. Further, ePTFE isessentially inert, is operable across a large temperature range and canwithstand harsh environments. The hydrophobicity of these materials alsoensures that no liquid will escape the container in the event of aprematurely opened peel seal. For at least these reasons, ePTFE providescharacteristics which are preferable in comparison to other materials.

An ideal pore size for an ePTFE membrane may be between 0.1 micron (μm)to 0.5 μm, such as 0.15 μm to 0.45 μm, or 0.2 μm to 0.3 μm. An ePTFEmembrane having pore sizes in this range exhibits relatively efficientvapor transmission characteristics while maintaining a sterile barriercapable of eliminating the ingress of contaminants.

A reinforcing or backing material is designed to bond breathablematerial to non-breathable material without impairing the functionalityof the breathable membrane 406. The addition of a reinforcing or backingmaterial improves the structural integrity of the container. That is,the reinforcing material must bond with the breathable membrane, mustbond with the non-breathable material, and must have a pore size thatdoes not impede vapor transmission across the breathable membrane duringlyophilization. Exemplary reinforcing materials are preferably a 50:50polypropylene/polyethylene blend. In embodiments, however, preferableblend ratios may vary and may be between 40:60 and 60:40polypropylene:polyethylene. Such backing materials are advantageous,inter alia, for their transition glass temperatures which are low enoughto avoid material degradation during freezing at lyophilizationtemperatures, such as approximately −40° C.

In embodiments comprising a laminate, various additional or alternativeplastic films may be incorporated into the breathable membrane or to thebacking material to impart desired characteristics, such as favorableheat-sealing characteristics, improved permeability, or for overallmechanical strength.

HOD 404 is a semi-rigid, flat-sided elliptical fixture, captured withinthe breathable section 400 by HOD capture zones 406. HOD 404 is in anopen mode in its native state, disposed circumferentially within thecontainer cavity to facilitate a pathway for vapor flow betweennon-breathable section and breathable section 400. HOD 404 is positionedentirely within the breathable section 404, bridging portions ofbreathable membrane 408 and non-breathable material. Notably, inembodiments, HOD 404 shape is not limited, and various alternative HOD404 designs may be implemented, such as a modified rectangle or othershape capable of facilitating vapor flow between container sections.

In various embodiments, HOD 404 may be a rigid or a semi-rigid fixturecaptured within, or fastened to the outside of, the breathable section400 of the lyophilization container. The exact position of the HOD 404may vary. For example, the HOD 404 may be positioned entirely within thenon-breathable section, or within a region of non-breathable material ofthe breathable section. Alternatively, HOD 404 may extend into portionsof both non-breathable material and breathable material. In yet furtherembodiments, HOD 404 may be positioned and configured to assist in thecreation of the temporary seal between container sections. Preferably,HOD 404 is positioned proximate to the peelable region to minimize thedistance between the HOD 404 and the placement of an occlusion in thepeelable region 420. In the example shown, the nearest edge of HOD 404is positioned approximately 2.5 cm from nearest edge of the peelableregion 420. Nonetheless, HOD 404 placement may be further optimizedaccording to a particular container configuration or peelable region 420configuration.

HOD capture zone 406 is a portion of container material which protrudesin the width direction of the container and which serves as a pocket orcavity space in which HOD 404 is securely captured. In embodiments,aspects of the HOD capture zone 406 may be optimized. For instance, HODcapture zone 406 width or depth may vary according to a particularcontainer configuration or HOD 404 configuration. In embodiments, HODcapture zone 406 width may be as much as 20 percent greater than thewidth of the HOD 404. Similarly, HOD capture zone 406 depth may bebetween 1 mm and 6 mm, such as between 2 mm and 4 mm. In yet furtherembodiments, the shape of HOD capture zone 406 may vary. For example,certain embodiments may include squared aspects or convex aspects, andso on. Those of skill in the art will appreciate that variousoptimizations to the size and shape of HOD capture zone 406 are withinthe scope and spirit of this application.

Tear away tail 412 is a multi-function region of breathable section 400configured to contribute to the evolution of the container throughoutits lifecycle. As shown, tear away tail comprises a hanger hole 416 forhanging the container. Tear away tail 412 further forms a portion ofhandle recesses 414. Handle recesses 414 may cooperate with features ofcertain system components such as a gas fill fixture shown in FIG. 7 .For example, in embodiments handle recesses 414 may cooperate with afill fixture handle in order to secure the breathable section of thecontainer to the fill fixture during a gas fill procedure for thepurpose of eliminating clutter and to simplify the obtaining of systemmeasurements. Tear seam 418 allows an operator to manually remove tearaway tail 412 for disposal or for final attachment to non-breathablesection. That is, tear away tail 412 may ultimately be attached to thefinal container of product (i.e., the non-breathable section) usingconventional means, such as a heat-sealing machine used to make apermanent seam in the container.

FIG. 5 is a section view of the Hold Open Device (HOD) of the embodimentshown in FIG. 4 .

Referring to FIG. 5 , HOD 500 is a semi-rigid fixture having anessentially ovular or elliptic shape incorporating pointed ends and flatsides. In the embodiment shown, HOD 500 is captured within thebreathable section proximate to the peelable region. In otherembodiments, the HOD 500 may be coupled to the outside of the container.Although generally the HOD 500 is designed to reside in, or on theoutside of, the breathable section of the container, physicallyseparated from the subject liquid throughout the container life cycle,various further embodiments could include HOD 500 in the non-breathablesection.

Incorporation of the elliptic HOD 500 aids in the creation of a generousopen region above a thin, uniform structure of ice. Preferably, thethin, uniform ice structure has a thickness of from 6 mm to 13 mm, suchas 10 mm, to maximize the efficacy and efficiency of the container.Incorporating the HOD 500 assists in securing a generous vapor pathwaybetween the non-breathable section and the breathable section andreduces overall vapor pressure in the container during sublimation. HOD500 may also compliment the removal and/or creation of an occlusion inthe peelable region. For example, HOD 500 may impart a tautness tocontainer material which improves the reliability or quality of anocclusion. HOD 500 may likewise assist in the pulling apart of peelableregion surfaces during a removal of the occlusion, thereby facilitatinga re-creation of the vapor pathway between container sections. Thepulling apart of peelable region surfaces can be complicated by theexistence of ice formed on, or directly adjacent to, the occlusion as aresult of an inadvertent wetting of peelable region materials by thesubject fluid prior to the freezing step. Such wetting may be causedduring the filling step, or by movement of the container. In thisrespect, HOD may compliment other means employed to address problemsassociated with the pulling apart of peelable region surfaces describedherein, including material and related texture choices.

In the embodiment shown, HOD 500 comprises a semi-rigid high-densitypolyethylene (HDPE). In embodiments, however, several other rigid orsemi-rigid materials may be implemented. For example, silicone,polypropylene, polyethylene, polyvinyl chloride (PVC) or certain othersynthetic plastic polymers may be preferable HOD 500 material. Incertain embodiments, semi-rigid materials may be incorporated for theirability to flex in response to an occlusion of the peelable region. Insuch embodiments, HOD may compress to some degree upon occlusion of thepeelable region and may rebound toward an original shape upon removal ofthe occlusion. Such shape-memory behavior may assist in the maintainingof an open region above the subject liquid or ice and in the creation ofgenerous vapor pathway between container sections. This may beespecially pronounced in embodiments combining a semi-rigid HOD withother flexible container materials.

The external height of HOD 500 shown in FIG. 5 is 2 cm; however, inembodiments, external height may vary from 1.0 cm to 4 cm. The internalheight is approximately 1.8 cm; however, in embodiments, the internalheight may vary between 1 cm to 3 cm depending on the exactconfiguration and size of HOD. HOD width is the approximate width of thelyophilization container. HOD 500 depth is approximately 3.0 cm;however, in embodiments HOD depth may be between 0.5 cm and 5 cm. Theoverall size and shape of HOD 500 is not limited, and accordingly mayvary depending on the desired configuration of a particular embodiment.

FIG. 6 is a side section view of an alternative configuration of apeelable region according to an embodiment of the present application.

Referring to FIG. 6 , peelable region 600 includes top material 602; dam604; and a liquid 606.

In the embodiment shown in FIG. 6 , peelable region 600 is incorporatedinto a lyophilization container disposed horizontally on a lyophilizershelf. Top material 602 of peelable region 600 comprises non-breathablematerial and is positioned opposite the container cavity from dam 604.Dam 604 is a rigid or semi-rigid container feature capable ofmaintaining a segregation of the liquid 606 input to the non-breathablesection. Dam 604 height measured from the shelf of the lyophilizer canbe any height which exceeds the height of liquid input intonon-breathable section. In this respect, dam 604 prohibits the flow offluid from non-breathable section into breathable section, as shown inFIG. 6 .

Dam 604 shown in FIG. 6 comprises a dome shape; however, in embodiments,other dam designs may be desirable. For instance, dam designs includinga flat top, or dam designs configured to cooperate with a particularocclusion device or member may be desirable. Preferred dam 604 materialsinclude materials capable of forming a peelable seal with top material602, including but not limited to textured materials and materialsincluding an additive. In a preferred embodiment, dam 604 material isdissimilar to top material 602; however, in certain embodiments, dammaterial may be the same as top material. In yet further embodiments,dam features may be incorporated into a lyophilization containerdesigned to hang vertically. In embodiments, dam features may beincluded on one or both sides of a peelable region to maintain asegregation of the fluid input into the non-breathable section.

FIG. 7 is an illustration of a system for lyophilizing a fluid accordingto an embodiment of the present application.

Referring to FIG. 7 , the system 700 includes a gas fill fixture 702; alyophilization container 704; a lyophilization loading tray 706; and alyophilizer 708.

The lyophilization container 704 is a container as described inembodiments of this application. That is, container 704 is a flexible,multi-part container including a peelable seal in a peelable region.

System 700 may vary in embodiments. For example, system 700 embodimentsmay exclude the gas fill fixture 702 or the lyophilization loading tray706 altogether. In further embodiments, system 700 may employ componentswhich are differently configured than those shown. For instance,lyophilizer 708 may be used in conjunction with a freezer that is aseparate system component. As can be readily envisioned by one of skillin the art, various further modifications to the system or itsindividual components may be made based on, e.g., a particular containerconfiguration, or the like, and are accordingly within the scope andspirit of this application.

As noted, embodiments of the lyophilization container(s) describedherein are configured to continually evolve as the lyophilizationprocess moves through its cycle. Described below are exemplary workflowswhich illustrate and facilitate container evolution.

FIG. 8 is a workflow schematic illustrating a lyophilization processaccording to an embodiment of the present application.

Referring to FIG. 8 , in step 802, a subject fluid (e.g., blood plasma)is introduced into the non-breathable section of a container includingan intact, temporary peelable seal in a peelable region of thecontainer. In step 804, the fluid is frozen, creating a thin, uniformlythick structure of ice in the non-breathable section. In step 806,vacuum pressure is applied. In step 808, the peelable seal is openedonce a sufficient pressure differential exists between thelyophilization chamber and the cavity of the non-breathable containersection. Opening of the peelable seal creates a communication pathwaybetween container sections. In step 810, heat energy is applied. Thecombined application of vacuum pressure and heat energy facilitatessublimation and desorption, causing a phase change in the ice structurefrom the solid phase directly to the vapor phase. Vapor released fromthe ice structure then flows through the container cavity via theunoccluded peelable region and escapes through the breathable section,leaving the lyophilized plasma cake (i.e., the ice structure nowdehydrated as a result of lyophilization) in the non-breathable section.In step 812, the container is occluded in the peelable region to preventcontamination of the lyophilizate. In step 814, a permanent seam isoptionally created in the non-breathable material of the breathablesection between the occlusion and the HOD. In step 816, the container isoptionally divided at the permanent seam and the breathable section isdiscarded, leaving the lyophilized end-product in the non-breathablesection. In step 818, the tear away tail is optionally separated fromthe breathable section. In step 820, the tear away tail is optionallyattached to the non-breathable section.

Referring to step 802, the introduction of fluid may be referred to aspre-loading. During preloading, between 250 ml to 500 ml of fluid (e.g.,blood plasma) are inputted into the non-breathable section of themulti-part lyophilization container. The container is then placedhorizontally on the shelf of a lyophilizer, “front” or “top” side upwardfacing.

Referring to step 804, the fluid is frozen to a temperature ofapproximately −40° C. In embodiments, however, initial freezingtemperature may range from −30° C. to −60° C., such as between −40° C.to −50° C.

Referring to steps 806 to 810, the application of heat energy and vacuumpressure serves multiple functions. For instance, the application ofvacuum lowers the pressure in the lyophilization chamber causing apressure differential between the lyophilization chamber and the cavitywithin the non-breathable section of the lyophilization container. Thispressure differential, in turn, results in an expansion of thenon-breathable section of the container. Eventually, this expansion ofthe non-breathable section of the container causes a peeling apart ofthe peelable seal. In embodiments, the pressures required to achievethis phenomena may range from between 400 Torr and 100 Torr, such asbetween 250 Torr and 150 Torr. Once the peelable seal is sufficientlypeeled away, the heat energy and vacuum pressure continue to facilitatesublimation and desorption. Notably, although heat energy is applied instep 810 after peeling of the peel seal in step 808, alternativeembodiments may introduce heat energy along with the introduction ofvacuum pressure. A preferable drying temperature is approximately −25°C.; however drying temperature may range from −20° C. to −60° C., suchas between −20° C. to −40° C. Owing to the generous vapor pathwaybetween container sections and the large surface area of breathablemembrane in the breathable section, vapor from the ice structure escapesrelatively freely from the container. This, in turn, results coldertemperatures during lyophilization and therefore an improved quality ofthe final dry product. In addition, a diminution in sublimation times ascompared to conventional lyophilization techniques is realized. Further,embodiments result in reduced vapor pressures in, and an increase inmass transfer across, the breathable section, which may result in asufficient drying of the ice structure solely during a single dryingphase. That is, embodiments may obviate the need for the secondarydrying phase of traditional two-phase drying methods (i.e., desorption).

Referring to step 812, an occlusion is created in the peelable region ofthe container, creating a temporary seal between the breathable sectionand the non-breathable section. In embodiments, this occlusion iscreated using a clamp.

In optional step 814, a permanent seam is created in non-breathablematerial of the breathable section. The permanent seam isolates thelyophilized cake in the non-breathable section. In the schematic shown,permanent seam step 814 is a discreet step. That is, an ancillary pieceof equipment is used to create the permanent seam or seal. In furtherexamples, the creation of a permanent seam in step 814 may be integratedinto step 812. In such embodiments, the occlusion means (e.g., a clamp)may incorporate the permanent sealing means.

In optional step 816, the dividing of the container and removal of thebreathable section represents an evolution of the container into itsmost compact form. Removal of the breathable section eliminates thepotential for moisture and oxygen ingress into the dried product,thereby increasing shelf life and plasma stability. Additionally, thereduced size of the final lyophilizate container is more convenient foreach of transportation, storage, reconstitution and infusion.

In optional steps 818 and 820, respectively, the tear away tail ismanually torn away from the breathable section at the tear seal and isattached to the non-breathable section. In embodiments, step 818 may beperformed using the heat-sealing machine used to create the permanentseam in step 812.

The workflow of FIG. 9 represents the workflow of FIG. 8 with theaddition of various optional steps.

FIG. 9 is a workflow schematic illustrating a lyophilization processaccording to another embodiment of the present application.

Referring to FIG. 9 , in step 902, a subject fluid (e.g., blood plasma)is introduced into a non-breathable section of a flexible lyophilizationcontainer including an intact peelable seal in a peelable region of thecontainer. In step 904, the lyophilization container is optionallyinputted into a fill fixture. In step 906, air, inert gas (e.g.,nitrogen), or a pH regulating gas (e.g., CO₂) is optionally introducedinto the non-breathable section through a port in the port region (e.g.,a docking port). In step 908, the lyophilization container is optionallyattached to a loading tray for optimizing container performance duringlyophilization. In step 910, the liquid in the container is frozen,creating a thin, uniformly thick structure of ice in the non-breathablesection. In step 912, vacuum pressure is applied. In step 914, thepeelable seal is opened once a sufficient pressure differential existsbetween the lyophilization chamber and the cavity of the non-breathablecontainer section. Opening of the peelable seal creates a communicationpathway between container sections. In step 916, heat energy is applied.The combined application of vacuum pressure and heat energy facilitatessublimation and desorption, causing a phase change in the ice structurefrom the solid phase directly to the vapor phase. Vapor released fromthe ice structure then flows through the container cavity via theunoccluded peelable region and escapes through the breathable section,leaving the lyophilized plasma cake (i.e., the ice structure nowdehydrated as a result of lyophilization) in the non-breathable section.In step 918, the container is optionally backfilled with an inert gas toraise container pressure to partial atmospheric pressure. In step 920,the container is occluded in the peelable region to preventcontamination of the lyophilizate. In step 922, a permanent seam isoptionally created in the non-breathable material of the breathablesection between the occlusion and the HOD. In step 924, the container isoptionally divided at the permanent seam and the breathable section isdiscarded, leaving the lyophilized end-product in the non-breathablesection. In step 926, the tear away tail is optionally separated fromthe breathable section. In step 928, the tear away tail is optionallyattached to the non-breathable section.

Referring to optional step 904, a gas fill fixture is used to assist theoperator in filling the lyophilization container with a gas. That is,the lyophilization container is inputted into a gas fill fixture andsubsequently filled with a gas. The gas fill fixture provides anoperator with an indication of a correct gas fill volume. In anexemplary embodiment, the gas fill fixture shown in FIG. 7 may be used.In alternative embodiments, the exact configuration of the gas fillfixture is not limited and may vary according to a number of variablesincluding as container configuration, process parameters, etc.

In optional step 906, air (or nitrogen or another inert dry gas), or apH regulating gas (e.g., CO₂) is introduced into the lyophilizationcontainer. Air can be introduced to create a generous physicalseparation, i.e., a vapor space, between the container material and thepreloaded fluid. In exemplary embodiments, the introduction of a vaporspace may cause container pressure to reach between 0.3 Pound per squareinch (Psi) and 1.0 Psi, such as 0.5 Psi (approximately 26 mmHG).Advantageously, the creation of a vapor space in the container creates agenerous free surface for sublimation to occur and may reduce the amountof ice “sticking” to the container material during and after thefreezing step. A pH-regulating gas may be introduced to thelyophilization container to regulate pH. In an alternate embodiment, apH-regulating gas may be introduced during step 914 described below.

Referring to optional step 908, a loading tray or loading tray assembly(as shown in FIG. 7 ) is used to optimize container performance. Thatis, the lyophilization container is attached to a loading tray orloading tray assembly and subsequently loaded into the lyophilizer. Theloading tray or loading tray assembly includes features which optimizecontainer performance. In an exemplary embodiment, the loading trayshown in FIG. 7 may be used. In alternative embodiments, the exactconfiguration of loading tray is not limited and may vary according to anumber of variables including as container configuration, processparameters, etc.

In optional step 918, the lyophilization container is backfilled topartial atmospheric pressure with pH regulating gas (e.g., CO₂). Inexemplary embodiments, backfill pressure is 120 Torr (or 120 mmHG)absolute pressure. In embodiments, backfill pressure may range frombetween 40 mmHG and 200 mmHG, such as between 100 mmHG and 140 mmHG.Once at partial atmospheric pressure, the container is occluded, andthen permanently sealed in steps 918 and 920, respectively. Occlusionand/or sealing of the container while at a pressure lower thanatmospheric pressure causes the container to collapse and reduce itsvolume when the container is exposed to atmospheric pressure. Thisprocess also secures the pH regulating gas in the non-breathable portionand prevents an ingress of oxygen and moisture into the container. Sincethe resultant container has been occluded and/or sealed at a pressurethat is less than atmospheric pressure, and since final container volumewill be in a reduced volume condition once the vacuum of the lyophilizeris removed, the final lyophilized product can be stored and transportedmore easily. Backfilling in this manner is particularly applicable tocontainer embodiments having flexible materials or components since sucha diminution of container volume would not be possible with a rigid,inflexible lyophilization container.

In optional step 922, a permanent seam is created in the non-breathablematerial of the breathable section between the occlusion and the HOD. Inoptional step 924, the container is divided at the permanent seam andthe breathable section is discarded, leaving the lyophilized end-productin the non-breathable section. In optional step 926, the tear away tailis separated from the breathable section. In optional step 928, the tearaway tail is attached to the non-breathable section.

In the workflows described above, the means for creating the occlusionare not limited. For example, the occlusion means may comprise atwo-part clamp which is optionally a part of a loading tray assemblysuch as that shown in FIG. 7 . In further embodiments, occlusion meansmay be integrated into the flexible container, or may be a reusablepiece of equipment external to the container. In embodiments, occlusionmeans must be capable of creating a temporary impermeable orsubstantially impermeable seal between the non-breathable section andthe breathable section of the evolving multi-part lyophilizationcontainer.

The use of a physical barrier (e.g., a peelable seal) to segregate fluidin the non-breathable section from the breathable section according toworkflows described above eliminates the potential for fluid contactwith, and fouling of, the pores of breathable material in the breathablesection. Membrane fouling can disrupt the sublimation and desorptionaspects of lyophilization, thereby increasing total lyophilization timeand reducing the ability to obtain a viable lyophilizate. Accordingly,eliminating the potential for fouling leads to a relative increase invapor flow which, in turn, results in faster freeze drying, a colder icetemperature during primary drying due to an increased sublimativecooling effect and increased retention of proteins and clotting factors.

Moreover, because the lyophilization container is a closed, sterilesystem including sterile fluid pathways, embodiments enablelyophilization to occur in both non-sterile environments and in remotelocations. In this respect, for example, embodiments allowlyophilization to be performed on-site at an ordinary blood center asopposed to a traditional clean room facility. Container embodiments alsoallow flexibility for an operator to freeze and maintain a frozeninventory of plasma in a standard freezer, such as that found in typicalblood bank settings. At a later time, this previously frozen plasma canbe moved to the more specialized lyophilization instrument forsublimation and desorption. Such work flow flexibility results inimproved blood logistics and work flow within the blood bank.

A further advantage of embodiments described herein is the ability toremove the non-breathable section of the lyophilization containerpost-lyophilization. Isolation and removal of the breathable sectionpost-lyophilization results in the creation of a smaller, lighteraseptic container enclosing the final lyophilizate. The resultantcontainer is also both flexible and highly portable. Moreover, since thebreathable section is most vulnerable to moisture and oxygen ingress,its removal can be said to improve the shelf stability of thelyophilizate. The novel use of a temporary occlusion described hereinmakes this advantage possible. That is, in conventional systemsutilizing glass containers, a stopper is mechanically applied to a glasslyophilization container prior to the opening of the lyophilizer inorder to prevent an ingress of moisture and oxygen into the container.In contrast, present embodiments utilize the temporary occlusion toprevent an ingress of moisture and oxygen into the non-breathableportion of the container until a permanent seal can be made betweennon-breathable material portions of the front and back of the container.

The ability of embodiments herein to evolve container configuration, yetto remain a closed, sterile system throughout each phase of containerlifecycle is highly unique and advantageous in the lyophilization space.That is, the present embodiments evolve to achieve significantadvantages over conventional devices and methods during each of filling,lyophilization, transportation, storage, reconstitution and infusion.Accordingly, many of the attributes and advantages described herein arenot possible using conventional devices and approaches, which do notevolve and which require a clean room environment. Importantly in thisregard, the evolving, multi-part containers described herein should befurther considered evolving, multi-function containers insofar as thetype and arrangement of container elements allow the container toaccomplish various functions throughout its lifecycle.

Notwithstanding the various specific embodiments enumerated in thisdisclosure, those skilled in the art will appreciate that a variety ofmodifications and optimizations could be implemented for particularapplications. Additionally, the present application is not limited tothe lyophilization of blood or blood products. That is, the principlesof the present application may be applicable to the lyophilization ofmany fluids. Accordingly, various modifications and changes may be madein the arrangement, operation, and details of the methods and systems ofthe present application which will be apparent to those skilled in theart.

1-22. (canceled)
 23. A lyophilization container comprising: a firstportion including a first wall at least partially defining a firstcavity, the first wall including a non-permeable material; a secondportion including a second wall at least partially defining a secondcavity, the second wall including a permeable material; a seal betweenthe first portion and the second portion, the seal configured to movefrom a sealed configuration to an unsealed configuration; and an openerproximate the seal and configured to maintain an opening in the firstcavity or the second cavity.
 24. The lyophilization container of claim23, wherein the seal is configured to move from the sealed configurationto the unsealed configuration based on a pressure differential betweenthe interior of the first cavity or the second cavity and the exteriorof the lyophilization container.
 25. The lyophilization container ofclaim 23, wherein when the seal is in the sealed configuration, thefirst cavity is fluidly isolated from the second cavity, and when theseal is in the unsealed configuration the first cavity is in fluidcommunication with the second cavity.
 26. The lyophilization containerof claim 23, wherein the opener includes a first longitudinal sidehaving a first end and a second end, and a second longitudinal sidehaving a first end and a second end, the first end of the firstlongitudinal side being fixed to the first end of the secondlongitudinal side, and the second end of the first longitudinal sidebeing fixed to the second end of the second longitudinal side.
 27. Thelyophilization container of claim 26, wherein the first longitudinalside and the second longitudinal side form an ovular or elliptical shapefrom a side view.
 28. The lyophilization container of claim 26, whereinthe first longitudinal side forms a dome shape and the secondlongitudinal side mirrors the shape of the first longitudinal side. 29.The lyophilization container of claim 23, wherein the opener is fixed tothe second wall in the second cavity proximate the seal.
 30. Thelyophilization container of claim 23, wherein the opener is between theseal and the permeable material.
 31. The lyophilization container ofclaim 23, wherein the opener is coupled to an outside of the second wallon the second cavity side of the seal.
 32. The lyophilization containerof claim 23, wherein the first cavity is configured to contain a solid,a liquid, a gas, or any combination thereof, and the second cavity isconfigured to contain only a gas.
 33. The lyophilization container ofclaim 23, wherein the opener is formed from high-density polyethylene(HDPE).
 34. The lyophilization container of claim 23, wherein the openeris formed of silicone, polypropylene, polyethylene, polyvinyl chloride(PVC), a synthetic plastic polymer, or any combination thereof.
 35. Thelyophilization container of claim 23, wherein the opener is formed froma semi-rigid material having shape-memory behavior.
 36. Thelyophilization container of claim 35, wherein the opener defines anexternal height within a range of about 1.0 cm to about 4.0 cm.
 37. Thelyophilization container of claim 35, wherein the opener defines aninternal height within a range of about 1.0 cm to about 3.0 cm.
 38. Thelyophilization container of claim 23, wherein the opener defines a depthwithin a range of about 0.5 cm to about 5.0 cm.
 39. A lyophilizationcontainer comprising: a first sheet and a second sheet, the first sheetbeing fixed to the second sheet along a perimeter of the second sheet todefine an internal space; a seal non-permanently adhering the firstsheet to the second sheet and at least partially defining a first cavityand a second cavity, the seal being configured to move from a sealedconfiguration to an unsealed configuration; and a fixture proximate theseal and configured to maintain an opening between the first sheet andthe second sheet.
 40. The lyophilization container of claim 39, whereinwhen the seal is in the sealed configuration, the first cavity isfluidly isolated from the second cavity, and when the seal is in theunsealed configuration the first cavity is in fluid communication withthe second cavity.
 41. The lyophilization container of claim 39, whereinthe fixture includes a first leg having a first end and a second end,and a second leg having a first end and a second end, the first end ofthe first leg being fixed to the first end of the second leg, and thesecond end of the first leg being fixed to the second end of the secondleg, such that the first leg and the second leg form an ovular orelliptical shape from a side view.
 42. The lyophilization container ofclaim 39, wherein the first sheet or the second sheet defining the firstcavity includes a non-permeable material and the first sheet or thesecond sheet defining the second cavity includes a permeable material,and the fixture is in the second cavity.